A multicentre, randomised, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (DESIREE).

BACKGROUND: Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc). PATIENTS AND METHODS: DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL). RESULTS: A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms. CONCLUSIONS: A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC. TRIAL REGISTRATION: ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099.

Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study).

BACKGROUND: The efficacy and toxicity of olaparib as combination therapy in early breast cancer (BC) patients with homologous recombinant deficiency (HRD) [score high and/or germline (g) or tumour (t) BRCA1/2 mutation] is not well described. GeparOLA (ClinicalTrials.gov, NCT02789332) investigated olaparib in combination with paclitaxel in HER2-negative early BC with HRD. PATIENTS AND METHODS: Patients with untreated primary HER2-negative cT2-cT4a-d or cT1c with either cN+ or pNSLN+ or cT1c and triple-negative breast cancer (TNBC) or cT1c and Ki-67>20% BC with HRD were randomised either to paclitaxel (P) 80 mg/m2 weekly plus olaparib (O) 100 mg twice daily for 12 weeks or P plus carboplatinum (Cb) area under the curve 2 weekly for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). Stratification factors were hormone receptor (HR) status (HR+ versus HR-) and age (<40 versus ≥40 years). The primary endpoint was pathological complete response (pCR; ypT0/is ypN0). A two-sided one-group χ2-test was planned to exclude a pCR rate of ≤55% in the PO-EC arm. Secondary end points were other pCR definitions, breast conservation rate, clinical/imaging response, tolerability and safety. RESULTS: A total of 107 patients were randomised between September 2016 and July 2018; 106 (PO N = 69; PCb N = 37) started treatment. Median age was 47.0 years (range 25.0-71.0); 36.2% had cT1, 61.0% cT2, 2.9% cT3, and 31.8% cN-positive tumours; grade 3 tumours: 86.8%; Ki-67>20%: 89.6%; TNBC: 72.6%; confirmed gBRCA1/2 mutation: 56.2%. The pCR rate with PO was 55.1% [90% confidence interval (CI) 44.5% to 65.3%] versus PCb 48.6% (90% CI 34.3% to 63.2%). Analysis for the stratified subgroups showed higher pCR rates with PO in the cohorts of patients <40 years and HR+ patients. CONCLUSION: GeparOLA could not exclude a pCR rate of ≤55% in the PO arm. PO was significantly better tolerated and the combination merits further evaluation.

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.

BACKGROUND: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. PATIENTS AND METHODS: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). RESULTS: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. CONCLUSIONS: Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02685059.

Treatment and outcomes of patients in the Brain Metastases in Breast Cancer Network Registry.

BACKGROUND: Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited. METHODS: We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions. RESULTS: Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p < 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p < 0.0001). CONCLUSIONS: Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.

Zoledronate for patients with invasive residual disease after anthracyclines-taxane-based chemotherapy for early breast cancer - The Phase III NeoAdjuvant Trial Add-oN (NaTaN) study (GBG 36/ABCSG 29).

BACKGROUND: Patients with invasive residual disease after neoadjuvant chemotherapy (NACT) are considered to have chemo-resistant breast cancer. Bisphosphonates are an established treatment for bone metastases and are of potential benefit as adjuvant treatment in early breast cancer. PATIENTS AND METHODS: Patients who had invasive tumour residuals (ypT1-4 and/or ypN+) after a minimum of four cycles of anthracycline-taxane-containing NACT were eligible for the NeoAdjuvant Trial Add-oN study. Patients were randomised within 3 years after surgery to receive zoledronate 4 mg i.v. for 5 years versus observation. Zoledronate was given every 4 weeks for the first 6 months, every 3 months for the following 2 years, and every 6 months for the last 2.5 years. Primary objective was disease-free survival. RESULTS: After a median time of 54.7 months no difference in disease-free survival was observed between the zoledronate and observation groups (hazard ratio [HR] 0.960, 95% confidence interval [CI] 0.709-1.30, log rank P=0.789). Various subgroups were examined without identifying a treatment effect of zoledronate. Patients over 55 years of age showed a HR of 0.832 in favour of zoledronate, but the result was not significant (P=0.480). A similar result was obtained for overall survival with a HR of 1.19 (95% CI 0.79-1.79; log rank P=0.408). Zoledronate was well tolerated and no new toxicity signal was identified. CONCLUSION: Postneoadjuvant treatment with zoledronate does not improve outcome in patients without pathological complete response after neoadjuvant anthracycline-taxane-based chemotherapy for early breast cancer.

The impact of second to sixth line therapy on survival of relapsed ovarian cancer after primary taxane/platinum-based therapy.

BACKGROUND: Despite recent progress in the treatment of ovarian cancer, the majority of patients eventually relapse. There is little information on the effectiveness of chemotherapy in higher treatment lines. PATIENTS AND METHODS: Characterization of the second to sixth line therapy and its effects on survival was carried out, based on data of n = 1620 patients from three large randomized phase III trials investigating primary therapy. RESULTS: Median progression-free survival (PFS) after the first, second, third, fourth and fifth relapse was 10.2 [95% confidence interval (CI) 9.6-10.7], 6.4 (5.9-7.0), 5.6 (4.8-6.2), 4.4 (3.7-4.9) and 4.1 (3.0-5.1) months, respectively. Median overall survival (OS) after the first, second, third, fourth and fifth relapse was 17.6 (95% CI 16.4-18.6), 11.3 (10.4-12.9), 8.9 (7.8-9.9), 6.2 (5.1-7.7) and 5.0 (3.8-10.4) months, respectively. The most frequent second and third line chemotherapy was platinum combination (n = 313, 24.5%) and topotecan (n = 118, 23.6%), respectively. Relapse treatment improved PFS and OS at the second to fourth recurrence, although frequently not performed according to the standard of care. In multivariate analysis, platinum sensitivity and optimal primary tumor debulking were revealed as independent prognostic factors for PFS up to third relapse. CONCLUSION: A maximum of three lines of subsequent relapse treatment seems to be beneficial for patients with recurrent ovarian cancer. Optimal primary tumor debulking and platinum sensitivity remain independent prognostic factors even after more frequent relapses.

Intraperitoneal treatment with the trifunctional bispecific antibody Catumaxomab in patients with platinum-resistant epithelial ovarian cancer: a phase IIa study of the AGO Study Group.

OBJECTIVE: The aim of this study was to select the best catumaxomab regimen for further investigation in ovarian cancer based on confirmed tumour response. METHODS: Randomised open-label phase IIa study in women with platinum-resistant or -refractory epithelial ovarian cancer. Catumaxomab (6-hour intraperitoneal infusion on days 0, 3, 7 and 10) was administered at a low (10, 10, 10 and 10 µg) or high dose (10, 20, 50 and 100 µg). Responders were patients with either a complete (CR) or partial (PR) response. RESULTS: Forty-five patients were randomised to receive either low dose (23) or high dose (22). There were no responders in the low-dose versus one patient (5%) in the high-dose group with a PR. In the low-dose group, two patients (9%) had stable disease compared with five patients (23%) in the high-dose group. Catumaxomab was well tolerated and there was no difference between the dose groups in the incidence of treatment-induced adverse events, the most common of which were gastrointestinal and injection-site reactions. CONCLUSION: Catumaxomab had modest activity in platinum-resistant ovarian cancer. The high-dose regimen was associated with a slightly better therapeutic index than the low dose regimen.

Combination therapy with pegylated liposomal doxorubicin and carboplatin in gynecologic malignancies: a prospective phase II study of the Arbeitsgemeinschaft Gynäekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and Kommission Uterus (AGO-K-Ut).

OBJECTIVE: A multicenter non-randomized phase II study was initiated to evaluate tolerability and efficacy of pegylated liposomal doxorubicin (PLD) in combination with carboplatin in gynecologic malignancies. METHODS: One hundred forty women with recurrent or advanced endometrial (n=31), cervical or vaginal cancer (n=31), uterine sarcomas (n=11), or recurrent platinum-sensitive ovarian cancer (n=67) received six courses of PLD 40 mg/m2 and carboplatin (AUC 6) every 28 days. RESULTS: Hematological toxicities with NCI-CTC grade 3/4 were anemia in 8%, thrombocytopenia in 14%, neutropenia in 24%, and febrile neutropenia in 2% of 652 cycles. Grade 3/4 non-hematological toxicities included fatigue (14% of patients), pain (10%), dyspnea (9%), palmar-plantar erythrodysesthesia (7%), and nausea/vomiting (7%). Dose intensity reached 87.2% for PLD and 88.2% for carboplatin. Seventy-four percent of all non-progressive patients received at least 5 cycles. Overall response rates were (116 patients evaluable for response): ovarian cancer (n=54) 68%, endometrial cancer (n=27) 44%, uterine sarcomas (n=9) 33%, and cervical/vaginal cancer (n=26) 12%. Median progression-free survival was 11.6 months (95%CI 9.6-14.1) for ovarian cancer and 9.5 months (95%CI 6.6-12.6) for endometrial cancer. Median overall survival was 23.8 months (95%CI 19.0-30.2) and 21.4 months (95%CI 11.9-), respectively. CONCLUSIONS: The combination of PLD and carboplatin was well tolerated and feasible in patients with gynecologic malignancies. Efficacy was low in cervical/vaginal cancer, but promising in patients with endometrial cancer. Efficacy was within the expected range in recurrent platinum-sensitive ovarian cancer and is currently under further investigation in a prospective randomized phase III trial comparing PLD/carboplatin with paclitaxel/carboplatin (CALYPSO-trial; AGO-OVAR 2.9).

Interstitial nephritis and high titers of PR3-ANCA: an unusual manifestation of ANCA-associated disease.

We present the case of a 75-year-old female with weight loss, anemia, systemic signs of inflammation, mild renal insufficiency, microscopic hematuria, mixed glomerular and tubular proteinuria, and high titers of PR3-ANCA. Renal biopsy demonstrated interstitial nephritis with some sclerosed but otherwise normal glomeruli. Extensive work-up showed no signs of granulomatous inflammation or other vasculitic organ involvement. We presumed this to be a rare renal manifestation of ANCA-associated disease with the presence of sclerosed glomeruli suggesting a previous history of glomerular involvement. In view of the absence of active vasculitic or granulomatous disease, treatment was limited to low-dose corticosteroids with good response.

[Health care ethics committees in German university clinics. A survey of all medical directors and directors of nursing]. / Klinische Ethikkomitees an deutschen Universitätskliniken. Eine Befragung aller Arztlichen Direktoren und Pflegedirektoren.

OBJECTIVE: Health Care Ethics Committees (HEC) are new ways of implementing clinical ethics in hospitals and nursing homes. In the US all health care institutions must provide some structure to handle ethical conflicts in everyday patients' care. However, in Germany only a minority of hospitals, often members of the Protestant or Catholic Hospital Associations, have founded HEC. No studies exist in regard to the situation at German university hospitals. METHODS: In November 2002 we posted a questionnaire with 13 items to all medical directors (M) and directors of nursing (N) of the 36 German university hospitals. RESULTS: The response rate was 82 %. Limitation of treatment, informed consent and the conflict between beneficience and autonomy are the most relevant ethical issues in everyday practice. N estimated the need for additional support of their staff in ethical issues higher than M. Improvement of interdisciplinary teamwork, further education in ethics and ethical guidelines have been identified in order to improve ethical professional performance. However, N mentioned the lack of time and the low priority of ethics more often than M as problems in implementing theses measures. Five German university hospitals are planning to establish a HEC and two hospitals want to employ a clinical ethicist. CONCLUSION: Our data show a high need for information about HEC in German university hospitals. The tasks, working methods and chances for further development of HEC are neither known nor used in the majority of German university hospitals.

Apheresis in lupus nephritis.

Systemic lupus erythematosus is a chronic autoimmune disease which commonly involves the kidneys. Despite great improvement in survival over the past years due to immunosuppressive therapy, renal failure remains an important cause of morbidity and mortality. In view of the pathogenesis of lupus nephritis, the use of less toxic and more specific ways of treatment such as the extracorporeal removal of pathogenetically relevant autoantibodies seems rational. On the basis of currently available studies, plasma exchange used alone or as an adjunct to conventional immunosuppressive therapy offers no clear benefit over standard immunosuppression in patients with active lupus nephritis and therefore cannot be recommended. However, although not proven, plasmapheresis might be beneficial in patients with acute life-threatening disease, for which high-dose immunosuppressive therapy may not be possible, or as an adjunct procedure for patients not responding to conventional therapy. Rather than the unselective removal of plasma, adsorption procedures allow the selective or specific removal of immunoglobulins, which seems to be a more reasonable approach in lupus nephritis. The results of the first clinical trials using different adsorption columns seem promising, but their use cannot be recommended until well-designed, case-controlled studies have been performed to prove their usefulness and cost effectiveness in lupus nephritis. So far, clear-cut recommendations regarding type of adsorption column, intensity and duration of treatment, and accompanying immunosuppressive treatment cannot be given.

Therapeutic plasma exchange in the intensive care setting.

The potential to treat life-threatening conditions with therapeutic plasma exchange (TPE) is limited to a few situations. In severe pulmonary hemorrhage as a complication of several immune disorders (e.g., antiglomerular basement membrane antibody disease, Wegener's granulomatosus, lupus erythematosus), TPE should only be considered after conventional measures (mostly pulses of methylprednisolone) have been applied. Idiopathic familial and nonfamilial thrombotic thrombocytopenic purpura as well as the subset of the hemolytic uremic syndrome not associated with diarrhea are clear indications for TPE using fresh frozen plasma as replacement fluid. Patients with myasthenic crisis will also benefit from TPE and will improve within 1 day. Acute pancreatitis as a complication of the chylomicronemia syndrome has a poor prognosis and should be treated with TPE without any delay. In the case of drug overdose or intoxication, the efficiency of TPE to remove the offending drug is usually overestimated. In this situation, TPE is useful only when the plasma protein binding of the substance is high (>80%) and the volume of distribution is low (<0.2 L/kg body weight). TPE is not without risks and hazards (e.g., vascular access, bleeding, allergy), which should also be considered when discussing this extracorporeal therapy in otherwise refractory clinical conditions.

[Wegener granulomatosis and microscopic polyangiitis. Diagnostic and clinical results in 54 patients with long-term follow-up]. / Wegener Granulomatose und mikroskopische Polyangiitis: Diagnostische und klinische Ergebnisse bei 54 Patienten im Langzeitverlauf.

BACKGROUND AND OBJECTIVE: Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) are primary necrotizing ANCA associated systemic vasculitides with preferential involvement of small and medium-sized vessels. It was the aim of this study to evaluate retrospectively data regarding diagnostic and clinical features collected over a long period on patients with WG and MPA at one medical centre. Additionally, the question was addressed whether both diseases are being more frequently diagnosed since the introduction of serological tests for ANCA. PATIENTS AND METHODS: The files of all patients with WG (n = 48) and MPA (n = 6) seen between 1976 and 1997 by our nephrology team were evaluated with respect to clinical presentation (signs and symptoms, outcome, complications) and relevant laboratory data (e.g. blood count, ESR, renal function, CRP, ANCA). RESULTS: Five of 48 patients with WG (24 males, 24 females, 22-67 and 18-77 years) had been diagnosed with the disease in the first 10 years before and 43 after ANCA serology became available. All MPA cases (6 males) had been diagnosed after 1992 and showed renal involvement. The pattern of organ involvement in this cohort with WG was the same as that recorded in the literature. Laboratory tests revealed raised ESR in 85%, anemia in 79%, ANCAs in 91% and increased CRP in 73%. A localized form of WG had been present in 15% of patients, the generalized in 85%. Treatment of the generalized form largely followed the Fauci scheme, achieving remission in 97%. After one year of immunosuppressive treatment 93% of patients with WG were still alive, 74% after 5 years. CONCLUSION: This is the first report in Central Europe to have analysed data on patients with WG and MPA, followed up for 20 years at one centre. There were no significant differences in the pattern of organ involvement, results of treatment and prognosis from previously published multicenter studies. Our data demonstrate that the diagnosis of WG has been more frequently made since the introduction of immunological tests for ANCA.